A double edged-sword - The Complement System during SARS-CoV-2 infection

Abstract

In the past 20 years, infections caused by coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 have posed a threat to public health since they may cause severe acute respiratory syndrome (SARS) in humans. The Complement System is activated during viral infection, being a central protagonist of innate and acquired immunity. Here, we report some interactions between these three coronaviruses and the Complement System, highlighting the central role of C3 with the severity of these infections. Although it can be protective, its role during coronavirus infections seems to be contradictory. For example, during SARS-CoV-2 infection, Complement System can control the viral infection in asymptomatic or mild cases; however, it can also intensify local and systemic damage in some of severe COVID-19 patients, due to its potent proinflammatory effect. In this last condition, the activation of the Complement System also amplifies the cytokine storm and the pathogenicity of coronavirus infection. Experimental treatment with Complement inhibitors has been an enthusiastic field of intense investigation in search of a promising additional therapy in severe COVID-19 patients.

Keywords: COVID-19; Complement System; Complement inhibitors; Inflammation; SARS-CoV-2.

Graphical abstract

Fig. 1

Complement System Activation. Alternative Pathway: Factor B (FB) bound to C3b is cleaved by Factor D (FD) into Ba and Bb fragments. The C3 convertase (C3bBb) cleaves C3 into C3a and C3b. The C5 convertase (C3bBbC3b_n) cleaves C5 into C5a and C5b fragments. For simplicity, the C3 convertase C3(H₂O)Bb is not represented here. Classical Pathway: once C1q binds to the immunocomplex, C1r is activated and subsequently activates C1s. Activated C1s cleaves C4 and C2, generating the C3 convertase (C4b2a) which cleaves C3 into C3a and C3b. When C3b fragments bind to the C4b2a, a C5 convertase (C3b2aC3b_n) is formed. Lectin Pathway: once mannose binding lectin (MBL) or ficolins bind to targets, the MBL associated serine proteases (MASP)-1, MASP-2, MASP-3 are activated, which leads to the cleavage of C4 and C2, resulting in the formation of C3 convertase and later C5 convertase, similar to those generated in the Classical Pathway. Membrane Attack Complex (MAC; C5b-9_n): C5 convertase cleaves C5 into C5a and C5b fragments. C5b binds to C6 and later to C7. C8 binds to C5b67 and several C9 molecules are incorporated (C5b6789_n). The production of MAC can be blocked by Complement inhibitors such as AMY 101 and APL-6 that interact with C3 and prevent its cleavage into C3a and C3b. Eculizumab, Zilucoplan, Ravulizumab and Tesidolumab are antibodies that blockage the cleavage of C5. Vilobelimab: anti-C5a antibody. Avdoralimab: anti-C5aR antibody. This figure was created using Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License: https://smart.servier.com. Adaptations from the original art were made on the cell membrane and macrophages.

Fig. 2

Biological functions of the Complement System. Antibody production: CR2 expressed in B lymphocytes and follicular dendritic cells interacts mainly with C3d fragments covalently bound to the pathogen surface, activating B lymphocytes, and increasing antibody production. Opsonization: C3b and iC3b are responsible for covalently attaching to the surface of different pathogens and they interact with Complement receptors CR1, CR3 and CR4 present on the surface of phagocytic cells such as neutrophils and macrophages, facilitating phagocytosis. Inflammation: the anaphylatoxins C3a and C5a are powerful chemoattractants to inflammatory cells and induce the release of mediators that amplify the inflammatory response. They perform different functions such as stimulation of mast cells and basophils, causing their degranulation, and release of inflammatory mediators, increased vasodilation, activation of complex inflammasomes and cytokine secretion. Cell activation: the anaphylatoxins are responsible for recruitment and activation of inflammatory cells, including eosinophils, neutrophils, basophils, monocytes and B lymphocytes. Cell Lysis: the formation of the Membrane Attack Complex (C5b-9_n) causes cell lysis. Immune Complexes Clearance: immune complexes covalently attached to C3b or C4b fragments binds to CR1 present on the surface of blood cells and are removed from circulation. This figure was created using Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License: https://smart.servier.com. Adaptations from the original art were made on the cell membrane and macrophages.

Fig. 3

A double-edged sword – The Complement System during SARS-CoV-2 infection. During early infection (left panel) the Complement System is immediately activated in lung after SARS-CoV-2 invasion, triggering membrane attack complex (MAC) formation which may cause virus lysis (A). Circulating leukocytes migrate to the inflammatory site attracted by the presence of C3a and C5a. These fragments also trigger the release of inflammatory mediators by mast cells (B). SARS-CoV-2 coated with C3b or iC3b bind to Complement Receptor (CR) 3 present in phagocytic cells. As a consequence, they can be internalized and killed by local macrophages (C). In most cases, these three steps effectively control infection, which is observed in asymptomatic individuals or patients with mild symptoms. In severe patients (right panel) an intense inflammatory response is observed locally followed by cytokine storm and intense production of neutrophil extracellular traps (NET) induced by C3a and C5a (D). In the presence of MAC, endothelial cells secrete von Willebrand factor which increases prothrombinase activity. This may contribute to fibrin deposition and endothelial injury (cell swelling and damage). Mannose binding lectin-associated serine protease (MASP)-1 and MASP-2 can cleave prothrombin and activate fibrinogen and factor XIII. The induction of endothelial P-selectin by C5a is important for the recruitment and aggregation of platelets. The intense NET production stimulated by C3a and C5a is pro-coagulant, resulting in platelet aggregation, coagulation and thrombi formation (E). This exacerbated inflammatory condition leads to bronchial infiltration, followed by C5 activation. In this way, hyperactivation of the Complement System can contribute to several pathologies such as cytokine storm and tissue damage experienced by patients with severe COVID-19. This figure was created using Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License: https://smart.servier.com. Adaptations from the original art were made on the cell membrane and macrophages.